Epidermis, cornification, keratinization Flashcards
1
Q
What keratins are expressed by basal keratinocytes in dogs?
A
K5, K14, K1, K6 (5+14 are the main ones to know)
2
Q
How many cells are included in the epidermal proliferative unit model of epidermal stem cell division?
A
10 cells (in basal layer)
3
Q
What population of cells is unique to the epidermal proliferative unit?
A
Transit amplifying cells - these proliferate rapidly to produce terminally differentiating cells in the epidermis
4
Q
Name the layers of the epidermis (deep to superficial)
A
Basale - spinosum - granulosum - corneum
5
Q
What makes up the spines of the cells in the stratum spinosum?
A
Desmosomes
6
Q
What proteins and keratins start to be produced in the spinous cell layer?
A
K1, K10, involucrin, profilaggrin
7
Q
What are keratohyalin granules?
A
Accumulations of synthesized proteins and lipids needed for the SC (primarily profilaggrin, loricrin, KIF)
8
Q
In what layer of the epidermis do the KIF begin to assemble?
A
Stratum granulosum
9
Q
In what layer does construction of the cornified envelope begin?
A
Stratum granulosum
10
Q
Where are the contents of lamellar granules released?
A
Interface between stratum granulosum and stratum corneum
11
Q
What does the cornified cell envelope take the place of?
A
Plasma membrane
12
Q
What type of filament of the epithelial cell cytoskeleton is the largest?
A
Microtubules (20 nm diameter)
13
Q
What type of filament of the epithelial cell cytoskeleton is the smallest?
A
Microfilaments (7 nm diameter, composed of actin)
14
Q
Describe the structure of keratin proteins
A
Central alpha-helical rod domain, amino-terminal head, and carboxy-terminal tail
15
Q
What type of keratins are acidic?
A
Type I (K9-19)
16
Q
What type of keratins are basic or neutral?
A
Type II (K1-8)
17
Q
What protein binds KIFs, facilitating the flattening of cornified cells?
A
Filaggrin
18
Q
What is the general term for filaggrin degradation products?
A
Natural moisturizing factors
19
Q
What are the products of filaggrin degradation?
A
AAs
urocanic acid
pyrrolidone carboxylic acid
lactic acid
citrate
sugars
20
Q
What enzyme is required for filaggrin degradation?
A
Caspase-14
21
Q
An increase in which intracellular ion results in increased transglutaminase activity?
A
Calcium
22
Q
What enzymes catalyze the formation of bonds which cross-link involucrin to other CE proteins?
A
Transglutaminases 1+3
23
Q
What protein is the major structural component of the cornified envelope?
A
Loricrin (70% of CE mass)
24
Q
What enzyme cross-links loricrin to small proline-rich peptides?
A
Transglutaminase 3
25
What enzyme cross-links the loricrin+proline-rich peptide oligomers to the CE?
Transglutaminase 1
26
What protein helps traffic lamellar granules from the Golgi network to the plasma membrane?
CHEVI complex
(C-homologues in endosome-vesicle interaction)
27
What is the primary signal that induces lamellar granule secretion between the granular and cornified layers?
Increased intracellular calcium
28
What converts glucosylceramides into ceramides in the intercellular lamellae?
beta-glucocerebrosidase
29
What are the breakdown products of phospholipids?
FFAs, glycerol
30
What is the function of glycerol in the SC?
hydration (hygroscopic molecule)
31
What is the function of FFAs in the SC?
acidification -- important for enzyme functions (esp beta-glucocerebrosidase and acidic sphingomyelinase)
32
What is the breakdown product of sphingomyelin?
ceramides
33
What enzyme converts sphingomyelin into ceramides?
acidic sphingomyelinase
34
What are the major lipid classes in the SC?
ceramides (50% of lipid mass)
FFAs (25% of lipid mass)
cholesterol (15% of lipid mass)
35
What group of ceramides is unique to the SC?
omega-hydroxyceramides (ceramides 1, 4, 9)
36
What are omega-hydroxyceramides bonded to?
involucrin, envoplakin, periplakin (help make up the cornified lipid envelope)
37
What would be the clinical manifestation of a malformation of the cornified lipid envelope?
Ichthyosis
38
What two enzymes are the key rate limiting enzymes in FFA synthesis?
acetyl-CoA carboxylase, fatty acid synthase
39
What fatty acids are NOT synthesized by the epidermis?
omega-3+6 polyunsaturated EFAs (i.e. linoleic acid and alpha-linolenic acid)
40
What specific fatty acids must be supplied by the diet/topicals?
linoleic acid (omega 6 PUFA)
alpha-linolenic acid (omega 3 PUFA)
41
What is the rate-limiting enzyme in cholesterol synthesis?
hydroxymethylglutaryl CoA reductase (HMG CoA)
42
What are two possible outcomes that happen to cholesterol synthesized in the lower epidermis?
1) Some is incorporated into lamellar granules and secreted into SG-SC interface unchanged
2) Some is sulfurylated, diffuses across membrane, and is metabolized back to cholesterol
43
What enzyme converts cholesterol sulfate back to cholesterol
Steroid sulfatase
44
Where does steroid sulfatase come from?
Secreted by lamellar granules
45
What is the role of cholesterol sulfate?
Inhibits serine proteases involved in desquamation
46
What is the desmoglea?
Extracellular part of desmosomes between adhered keratinocytes
47
Which desmosome plaque is intertwined with KIFs?
Inner dense plaque
48
What desmosome plaque borders the plasma membrane?
Outer dense plaque
49
What proteins are the transmembrane molecules that form an adhesive interface between neighboring keratinocytes?
Cadherins
50
What cadherins comprise the desmoglea?
Desmogleins
Desmocollins
51
What protein family binds to the cytoplasmic portion of cadherins?
Armadillo proteins (Plakoglobin, plakophilin)
52
What protein binds desmoplakin and cadherins?
Plakoglobin
53
What protein facilitates lateral linkage between desmoplakins?
Plakophilin
54
What protein binds KIFs to plakoglobin?
Desmoplakin
55
What do corneodesmosomes contain?
Desmoglein 1, desmocollin 1, corneodesmosin
56
What proteins in the epidermis are known to have glycine loops?
Keratins, loricrin, corneodesmosin
57
What is the function of glycine loops?
Mediate reversible and adjustable adhesion (acts like Velcro not glue)
58
Where is corneodesmosin synthesized?
In the granular keratinocyte
59
Where is corneodesmosin secreted?
Into the intercellular space starting in the SECOND layer of the SG
60
What protein is progressively cleaved as corneocytes advance towards desquamation?
Corneodesmosin
61
How does corneodesmosome distribution differ between lower and upper SC?
Lower SC: corneodesmosomes are all around the KC surface
Superficial SC: corneodesmosomes are only at periphery of KC
62
What is responsible for the superficial basket-weave of the layers of the upper SC?
Corneodesmosome distribution limited to periphery of cells in the upper SC
(deeper SC appears more compact microscopically because corneodesmosomes are all around the KC)
63
What transmembrane molecules make up epidermal tight junctions?
Claudins
Occludins
64
Which claudins are expressed in the epidermis?
Claudins 1, 4, 7
65
Which intracellular proteins help make up epidermal tight junctions?
zonula occludens proteins
66
Where are adherens junctions found on basal cells?
Lateral and apical membranes
67
Where are adherens junctions found on suprabasal cells?
entire cell surface
68
What junction links the actin cytoskeleton to the plasma membrane?
Adherens junctions
69
What protein classes are involved in adherens junctions?
Cadherins and catenins
70
How long does it take for complete renewal of the human epidermis?
28 days
71
What 2 protein classes are involved in desquamation?
kallikreins
Cathepsins
72
What proteins are cleaved by KLK5?
Corneodesmosin
Desmoglein 1
Desmocollin 1
73
What proteins are cleaved by KLK7?
Corneodesmosin
Desmocollin 1
74
Which KLK are involved in degrading corneodesmosomes?
KLK 1, 5, 6, 7, 14
75
Which KLK degrade desmoglein 1?
KLK 1, 5, 6, 14
76
What proteins cleave corneodesmosin?
KLK 5
Cathepsin L-like enzyme
Cathepsin D
77
What is the concentration of Ca2+ in the lower epidermis as compared to the upper epidermis?
Low in SB and SS, increased in SG, decreased again in SC
78
What structures provide a barrier to water loss in non-cornified epidermis?
Tight junctions
79
What structures regulate the Ca2+ gradient in the epidermis?
Tight junctions and the SC
80
What proteins provide most of the mechanical protection of the epidermis?
Keratins, filaggrin
81
What is the primary barrier to movement of electrolytes and water in the SC?
Extracellular lipid matrix (cholesterol, FFAs, ceramides)
82
What parts of the SC provide protection from UV radiation?
Byproducts of filaggrin metabolism
83
Describe the structure of phospholipids
Glycerol (head) + phosphate group (head) + 2 FAs (tail)
84
What is the optimal water concentration of the SC?
20-35%
85
Between which epidermal layers is the stratum lucidum found?
Between SC and SG
86
Is TEWL increased or decreased in dogs with atopy?
Increased
87
How do skin lipids in dogs and cats differ from humans?
Dogs and cats have more sterol esters, free cholesterol, and diester waxes
88
Describe the structure of a ceramide
FA linked to a sphingoid base
89
What protein helps incorporate glucosylceramide into lamellar granules?
ABCA12
90
What is the most abundant lipid in the body?
Cholesterol
91
What is the most abundant lipid in the SC?
Ceramides
92
Describe the structure of FFAs
Long carbon chain with a methyl group at one end
93
What protein is key in the uptake of FAs into keratinocytes?
Fatty acid transport protein (FATP4)
94
What type of lipid incorporates FFAs?
Ceramides
95
What food contains high levels of linoleic acid?
Plants
96
What are the essential fatty acids in cats?
Arachidonic acid linoleic acid
97
What food contains high levels of a-linolenic acid?
Fish
98
What are the metabolites of alpha-linolenic acid?
EPA, DHA
99
What type of fatty acids are anti-inflammatory?
Omega-3
100
What type of fatty acids are pro-inflammatory?
Omega-6
101
What are the essential fatty acids in dogs?
Linoleic acid, alpha-linolenic acid
102
What enzyme allows for free arachidonic acid to be released from the phospholipid membrane into the skin?
Phospholipase A2 (PLA2)
103
What enzyme is mutated in Harlequin ichthyosis?
ABCA12 (important for transfer of glucosylceramides into lamellar bodies)
104
What lipid changes occur between the SG and SC?
Phospholipids replaced by ceramides
Increase in free sterols
Increase in FFAs, decrease in triglycerides and phospholipids
105
What is the effect of increased pH on desquamation?
Increased protease activity --> increased desquamation
106
What is the pathogenesis of epidermolytic ichthyosis?
Defect in keratin formation
107
What is the mode of inheritance of ichthyosis in Norfolk Terriers?
Autosomal recessive
108
What breeds are predisposed to epidermolytic ichthyosis?
Norfolk Terriers, Rhodesian Ridgebacks, Labs
109
What gene is mutated in epidermolytic ichthyosis in Labs and Rhodesian Ridgebacks?
NSDHL
110
What is the pathogenesis of non-epidermolytic ichthyosis?
Defect in formation of lipid layer or cornified envelope
111
What gene is mutated in ichthyosis in Norfolk Terriers?
KRT10
112
What genes are mutated in ichthyosis in Golden Retrievers?
PNPLA1 (needed for CLE formation)
ABHD5
113
What gene is mutated in ichthyosis of American Bulldogs?
NIPAL-4 (cofactor for FATP4)
114
What gene is mutated in ichthyosis in JRTs?
Transglutaminase-1 (mediates Ca2+ dependent cross-linking of involucrin and loricrin to form cornified envelope)
115
What gene is mutated in ichthyosis in Great Danes?
SLC27A4 (encodes FATP4 synthesis)
116
What gene is mutated in ichthyosis in GSDs?
ASPRV1 (profilaggrin-filaggrin processing)
117
What breeds are predisposed to ARCI (autosomal recessive congenital ichthyosis)?
CKCS, Golden Retriever, JRT, Great Dane, American Bulldog
118
What form of ichthyosis in cattle is lethal?
Ichthyosis fetalis (bovine harlequin ichthyosis)
119
What cattle breeds are predisposed to Harlequin ichthyosis?
Chianina
Holstein-Friesian
Brown Swiss
Norwegian Red Poll
Hanwoo
Polled Hereford
Shorthorn
Belgian White and Red
120
What form of ichthyosis in cattle is mild?
Ichthyosis congenita
121
What breeds are predisposed to ichthyosis congenita in cattle?
Jersey
Pinzgauer
Holstein-Friesian
Chianina
122
What lipid is substituted into the phospholipid membrane in seborrhea?
Oleic acid (less flexible than linoleic acid)
123
What is the thickness (mm) of normal canine skin?
0.1-0.5 mm
124
Where might you find rete ridges in canine skin?
Footpads, nasal planum, scrotum
125
Where on the body is the stratum spinosum thickest?
Feet, nasal planum, MC junctions
126
Is the SG thicker in haired or non-haired skin?
Non-haired (4-8 cell layers thick)
127
Where is the stratum lucidum found?
Footpads and nasal planum only
128
What is the only epidermal layer that contains desmoglein 3?
Stratum spinosum
129
What cadherins are found in all layers of the epidermis?
Desmocollin-2
Desmocollin-3
E-cadherin
130
What cadherins are found only in the stratum basale?
Desmoglein-2
P-cadherin
131
What cadherins are in all layers of the epidermis EXCEPT the stratum basale?
Desmoglein-1
Desmoglein-4
Desmocollin-1
132
What is the primary scaffold protein of the cornified envelope?
Involucrin
133
What proteins makes up 80-90% of the epidermal mass?
Filaggin and keratin
134
What are the 4 distinct cellular events in cornification?
1) Keratinization
2) Keratohyalin synthesis
3) CE formation
4) Lamellar body synthesis
135
Where is K2 expressed?
Stratum granulosum
136
What is the molecular target in pemphigus vulgaris?
Desmoglein-3
137
What is the molecular target in lamellar ichthyosis?
transglutaminase-1
138
What is the molecular target in ectodermal dysplasia?
Plakophilin-1
139
What is the epidermal turnover rate in seborrheic Cocker Spaniels?
7 days
140
What is the epidermal turnover rate in normal canine skin?
22 days
141
What is the epidermal turnover rate in normal bovine skin?
18 days
142
What is the epidermal turnover rate in normal murine skin?
8-10 days
143
What is the molecular target in human PF?
Desmoglein-1
144
What is the molecular target in canine PF?
Desmocollin-1
145
What cell layer contains mitotic cells?
S. basale (other layers do not)
146
What layer of the epidermis contains tight junctions?
S. granulosum
147
What filaggrin breakdown product offers some UV protection?
Urocanic acid
148
A defect in which protein in cornification is known to be a major predisposing factor for the development of AD in humans?
Filaggrin
149
Where would a keratin 10 mutation most likely manifest in the epidermis?
Stratum spinosum/stratum granulosum
150
At which pH are kallikreins active?
Neutral
151
What is demonstrated on the right side of the photo below as compared to the left side?
Right side demonstrates ichthyosis: irregular arrangement of enlarged corneocytes with entombed lamellar body contents (arrowheads)
152
What is the mode of inheritance of ichthyosis in Labs?
X-linked semidominant
153
In which breed does ichthyosis result in non-viability shortly after birth?
Great Danes
154
What structure is attenuated or absent in both Golden Retriever and American Bulldog ichthyosis?
Cornified lipid envelope
155
What organism is likely to overgrow in ichthyosis?
Malassezia
156
What structure is lost or attenuated in ichthyosis in JRTs?
Cornified envelope (NOT the cornified lipid envelope)
157
What are the clinical signs of ichthyosis in CKCS?
KCS, rough curly coat, nail dystrophy, scaling
158
What is the mutation in paw pad hyperkeratosis in the dogues de Bordeaux?
KRT16
159
What is the mutation in paw pad hyperkeratosis in Irish terriers and Kronfohrlanders?
FAM83G
160
What is the mutation in hereditary nasal parakeratosis in Labs?
SUV39H2 (decreases expression of loricrin in the SC)
161
What is the primary function of bleomycin hydrolase and caspase 14?
degradation of intracellular filaggrin into free AAs
162
What occurs in the initiation phase of CE formation?
synthesis of CE structural proteins
163
What occurs in the reinforcement phase of CE formation?
attachment of lipids to CE proteins
164
What enzyme is essential to inhibit kallikreins in the intercellular space to prevent early desquamation?
LEKTI
165
Is sulfur keratolytic or keratoplastic?
Both
166
Is tar keratolytic or keratoplastic?
Both
167
Is benzoyl peroxide keratolytic or keratoplastic?
Keratolytic
168
Is selenium sulfide keratolytic or keratoplastic?
Both (and degreasing)
169
What is the typical age of onset of primary seborrhea?
12-18 months (though as early as 10 weeks)
170
What feline breed is predisposed to ulcerative nasal dermatitis?
Bengals
171
What is the average epidermal renewal time in cases of ichthyosis?
~3.6 days
172
What is the typical age of onset of ichthyosis in Golden Retrievers?
<1 year (though adult onset is reported)
173
Which breed has a form of ichthyosis that is homologous with lamellar ichthyosis in humans?
JRTs (TGM1 deficiency)
174
What gene is mutated in canine X-liked cornification defects and causes CHILD syndrome in people?
NSDHL (codes for a protein involved in cholesterol synthesis)
175
What is the typical distribution of X-linked cornification defect/CHILD syndrome on the skin?
Along Blaschko's lines
176
What breeds are predisposed to vitamin A-responsive dermatosis?
American Cocker Spaniels
Labs
Miniature Schnauzers
Gordon Setters
177
How should oral vitamin A be administered?
With a fatty meal
178
What is the proposed pathogenesis of psoriasiform-lichenoid dermatosis?
exaggerated reaction to Staph infection
179
Which breed is predisposed to psoriasiform-lichenoid dermatosis?
English Springer Spaniels
180
What dermal cell infiltrate is a main feature of psoriasiform-lichenoid dermatitis?
Plasma cells
(neutrophilic and eosinophilic microaggregates also present)
181
What are the clinical signs of Schnauzer comedo syndrome?
Non-painful, non-pruritic comedones on dorsal midlines between shoulders and sacrum
182
What mutation has been identified in footpad hyperkeratosis in Rottweilers?
DSG1 frameshift mutation
183
What breeds are predisposed to hereditary nasal hyperkeratosis?
Labs, Greyhounds
184
What is the mode of inheritance for sebaceous adenitis?
autosomal recessive
185
What cytokines are elevated in the skin during inflammation and would stimulate epidermal proliferation, leading to secondary seborrhea?
leukotriene B4, PGE2
186
What type of zinc-responsive dermatosis is more common in Arctic breed dogs?
Syndrome 1
187
What breed are predisposed to zinc-responsive dermatosis syndrome 2?
Rapidly growing large breeds
188
What can exacerbate zinc-responsive dermatosis?
Estrus (estrogen competes with zinc for serum proteins)
189
What is the gene mutation in lethal acrodermatitis of white bull terriers?
MKLN1
190
What is the mode of inheritance of lethal acrodermatitis?
Autosomal recessive
191
Does lethal acrodermatitis respond to zinc supplementation?
No
192
What are the cutaneous signs of lethal acrodermatitis?
Crusty exfoliative lesions of distal extremities, footpads, MC junctions, digits splayed
193
A male castrated dog presented with tail gland hyperplasia. What organ could be affected to cause this change?
Adrenal glands
194
A dog presents with unilateral xeromycteria. What is likely to be a concurrent clinical sign?
KCS
195
What nerve is affected in parasympathetic nasal hyperkeratosis?
Parasympathetic division of the facial nerve (CN 7)
196
What are the histopathologic features of exfoliative dermatitis?
CD3+ lymphocytic interface dermatitis
Orthokeratotic hyperkeratosis
Interface mural folliculitis
197
Describe the histopathologic features of SND
Parakeratosis (red)
Intra- and intercellular edema with hydropic degeneration (white)
Basal cell hyperplasia (blue)
198
What is the epidermal renewal time in horses?
17 days
199
What is the most common keratinization disorder in horses?
Cannon keratosis
